This invention relates to new pyrazolo[4,3-d]pyrimidine derivatives and to their use in suitable utilities, especially diagnostic and therapeutic methods.
The cell division cycle is usually regarded as a succession of two phases, the S phase (DNA synthesis) and the M phase (segregation of the synthesized DNA in the two daughter cells) interspaced by two gap periods, G1 and G2. The net result of the cell cycle scenario may not only be growth and differentiation, but also tumor development and apoptosis. This view reflects the evidence accumulated over the last 5 years in mammalian field, that the vast majority and quite likely all tumors have suffered one or more defects that derail the cell cycle machinery. Such defects can either target components of the cell cycle apparatus, including the checkpoint mechanisms that ensure fidelity and orderly progression through the cell cycle phases, thereby protecting genome, or target elements of the upstream signaling cascades, whose effects eventually converge to trigger cell cycle events (Bártek et al. 1999, J. Pathol. 187: 95-99).
Although the concept of cancer as a disease of the cell cycle implies that every tumor is defective in one or more aspects of all cycle control, it clearly does not mean that oncogenesis targets only the cell cycle clock. Development of a tumor appears to require also aberrations in the cell death machinery and cell-cell and/or cell-matrix interactions that co-operate with cell cycle defects. The above concept simply regards cell cycle deregulation as an essential step in the process of multistep tumorigenesis.
In terms of the molecular pathogenesis of tumors, cell cycle defects can either represent the initial, predisposing event, or contribute to tumor progression. Examples of tumor-predisposing alterations include, for instance, germ-line mutations of the CDK inhibitors p16INK4A or p57KIP2, while many of the known cell cycle defects result from somatic mutations or even epigenetic changes that may occur during the early or later stages of tumorigenesis (Hunter 1997, Cell 88: 333-346, Fearon 1997, Science 278: 1043-1050).
The importance of cell cycle regulatory proteins, their direct interaction with oncogenes and the tumor suppressor pRb and their frequent deregulation in human tumors has encouraged an active search for low-molecular weight regulators of these proteins. Among them the chemical inhibitors of cyclin-dependent kinases were the first discovered. These inhibitors are anti-mitotic and display very interesting antimitotic and anti-tumor activities.